Gout

Martin Underwood

. 2015 Mar 19;2015:1120.

Gout

Martin Underwood ¹

PMCID: PMC4365763 PMID: 25789770

Abstract

Introduction

Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments for acute gout? What are the effects of xanthine oxidase inhibitors to prevent gout in people with prior acute episodes? We searched: Medline, Embase, The Cochrane Library, and other important databases up to September 2013 (BMJ Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 21 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: colchicine, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), and xanthine oxidase inhibitors.

Key Points

Gout is characterised by deposition of urate crystals, causing acute monoarthritis and crystal deposits (tophi).

Gout affects about 5% of men and 1% of women, with up to 80% of people experiencing a recurrent attack within 3 years.
Definitive gout diagnosis is based on crystal identification in synovial fluid or tophus material. However, in routine practice, diagnosis is usually made clinically, supported by the presence of hyperuricaemia.
Risk factors are those associated with hyperuricaemia, including older age, non-white ethnicity, obesity, excess consumption of alcohol, meat, and fish, and use of diuretics.
Hyperuricaemia and gout may be independent risk factors for cardiovascular disease.

There is a lack of evidence from RCTs on the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) to reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects.

Indometacin may be more effective than celecoxib, and equally effective as etoricoxib, at reducing pain in people with acute gout, although indometacin may be associated with an increased risk of adverse effects compared to etoricoxib.

Colchicine may be more effective than placebo at improving symptoms in acute gout. Its use is limited by the high incidence of adverse effects, although these may be reduced with low-dose colchicine regimens.

Low-dose colchicine may also be effective at reducing pain in gout and may produce fewer adverse effects than high-dose colchicine.

There is a lack of evidence from RCTs concerning the effectiveness of intra-articular or parenteral corticosteroids to improve symptoms in acute gout.

Oral corticosteroids seem as effective as NSAIDs and may have fewer short-term adverse events.

It’s not clear from the evidence from RCTs if xanthine oxidase inhibitors are effective at reducing the risk of recurrent attacks in the long term when compared with placebo or other treatments. Higher doses of febuxostat may increase the risks of gout attacks compared with placebo, and compared with allopurinol.

Colchicine may reduce the risk of an attack in a person starting allopurinol treatment.

Clinical context

General background

Gout is a common problem in older people, affecting up to 5% of men aged 65 to 74 years in the UK; with an ageing population and increasing obesity, it is set to become more common. While there are established treatment patterns for gout, it is important to appreciate the quality of the evidence that underpins these and how this informs judgements about the balance of risks and benefits.

Focus of the review

The focus of this review is on the principal drug groups used for the treatment and prevention of acute gout. We have not considered the evidence for the treatment of hyperuricaemia in this review as it is symptomatic gout that has direct patient relevance. Whilst other drugs, including uricosurics, may reduce serum urate, they are not all easily available in different jurisdictions.

Comments on evidence

There are few robust data from RCTs to inform our management of gout. There are few placebo controlled trials of treatments for acute gout, mainly of poor quality; although, there are some good studies comparing active treatments. Notwithstanding evidence for reduction in serum urate, the therapeutic target, the evidence for reduction of recurrent gout over 1 year using xanthine oxidase inhibitors is weak.

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, September 2010, to September 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 179 studies. After deduplication and removal of conference abstracts, 92 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 61 studies and the further review of 31 full publications. Of the 31 full articles evaluated, two systematic reviews and two RCTs were added at this update.

Additional information

There is international consensus that reducing serum urate to less than 0.36 mmol/L should be the therapeutic target for prevention of gout using urate-lowering drugs, as this will allow crystals to be mobilised. This urate mobilisation may itself trigger gout. This is a possible explanation for the apparent paradox that effective urate reduction over 1 year does not reduce incidence of recurrent gout over the same period.

About this condition

Definition

Gout is a syndrome caused by deposition of urate crystals. It typically presents as an acute monoarthritis of rapid onset. The first metatarsophalangeal joint is the most commonly affected joint (podagra). Gout also affects other joints; joints in the foot, ankle, knee, wrist, finger, and elbow are the most frequently affected. Crystal deposits (tophi) may develop around hands, feet, elbows, and ears. Diagnosis definitive gout diagnosis is based on crystal identification in synovial fluid or tophus material. However, in routine practice, diagnosis is usually made clinically, supported by presence of hyperuricaemia. The American College of Rheumatology (ACR) criteria for diagnosing gout are as follows: (1) characteristic urate crystals in joint fluid; (2) a tophus proved to contain urate crystals; or (3) the presence of six or more defined clinical laboratory and x-ray phenomena (see table 1 ). We have included studies of people meeting the ACR criteria, studies in which the diagnosis was made clinically, and studies that used other criteria. Where possible, we have reported the study entry criteria.

Table 1.

American College of Rheumatology criteria for acute gout (people must fulfil at least 6 criteria).


1	More than 1 attack of acute arthritis
2	Maximum inflammation developed within 1 day
3	Monoarthritis attack
4	Redness observed over joints
5	First metatarsophalangeal joint painful or swollen
6	Unilateral first metatarsophalangeal joint attack
7	Unilateral tarsal joint attack
8	Tophus (proved or suspected)
9	Hyperuricaemia
10	Asymmetric swelling within a joint on x-ray film
11	Subcortical cysts without erosions on x-ray film
12	Joint culture negative for organism during attack

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Incidence/ Prevalence

Gout is more common in older people and men. In people aged 65 to 74 years in the UK, the prevalence is about 50/1000 in men and about 9/1000 in women. The annual incidence of gout in people aged over 50 years in the US is 1.6/1000 in men and 0.3/1000 in women. One 12-year longitudinal study of 47,150 male health professionals with no previous history of gout estimated that annual incidence of gout ranged from 1.0/1000 for those aged 40 to 44 years to 1.8/1000 for those aged 55 to 64 years. The global prevalence of gout is 0.076% (95% uncertainty interval 0.072% to 0.082%). There are wide regional variations in prevalence. The highest prevalence is in Australasia (0.389%, 95% uncertainty interval 0.354% to 0.428%). This compares with a prevalence of 0.205% in Western Europe (95% uncertainty interval 0.178% to 0.245%) and 0.242% in North American high-income countries (95% uncertainty interval 0.217% to 0.279%). Gout may be becoming more common because of increasing longevity, obesity, meat and fish consumption, and use of diuretics. Although there has been little change in global (age-standardised) prevalence, the disability-adjusted life years (DALYs) attributable to gout increased by 49% from 76,000 (95% credibility interval 48,000 to 112,000) in 1990 to 114,000 (95% credibility interval 72,000 to 167,000) in 2010. In the global burden of disease 2010 study, gout was ranked 173 out of 291 conditions studied for overall burden (DALYs).

Aetiology/ Risk factors

Urate crystals form when serum urate concentration exceeds 0.42 mmol/L. Serum urate concentration is the principal risk factor for a first attack of gout, although 40% of people have normal serum urate concentration during an attack of gout. A cohort study of 2046 men followed up for about 15 years found that the annual incidence was about 0.4% in men with a urate concentration of 0.42 mmol/L to 0.47 mmol/L, rising to 4.3% when serum urate concentration was 0.45 mmol/L to 0.59 mmol/L. One 5-year longitudinal study of 223 asymptomatic men with hyperuricaemia estimated the 5-year cumulative incidence of gout to be 11% for those with baseline serum urate of 0.42 mmol/L to 0.47 mmol/L, 28% for baseline urate of 0.48 mmol/L to 0.53 mmol/L, and 61% for baseline urate levels of 0.54 mmol/L or more. The study found that a 0.6 mmol/L difference in baseline serum urate increased the odds of an attack of gout by a factor of 1.8 (OR adjusted for other risk factors for gout: 1.84, 95% CI 1.24 to 2.72). One 12-year longitudinal study (47,150 male health professionals with no history of gout) estimated that the relative risks of gout associated with one additional daily serving of various foods (weekly for seafood) were as follows: meat 1.21 (95% CI 1.04 to 1.41), seafood (fish, lobster, and shellfish) 1.07 (95% CI 1.01 to 1.12), purine-rich vegetables 0.97 (95% CI 0.79 to 1.19), low-fat dairy products 0.79 (95% CI 0.71 to 0.87), and high-fat dairy products 0.99 (95% CI 0.89 to 1.10). Alcohol consumption of more than 14.9 g daily significantly increased the risk of gout compared with no alcohol consumption (RR for 15.0–29.9 g/day 1.49, 95% CI 1.14 to 1.94; RR for 30.0–49.9 g/day 1.96, 95% CI 1.48 to 2.60; RR for at least 50 g/day 2.53, 95% CI 1.73 to 3.70). The longitudinal study also estimated the relative risk of gout associated with an additional serving of beer (355 mL, 12.8 g alcohol), wine (118 mL, 11.0 g alcohol), and spirits (44 mL, 14.0 g alcohol). It found that an extra daily serving of beer or spirits was significantly associated with gout, but an extra daily serving of wine was not (RR for 355 mL/day beer 1.49, 95% CI 1.32 to 1.70; RR for 44 mL/day spirits 1.15, 95% CI 1.04 to 1.28; RR for 118 mL/day wine 1.04, 95% CI 0.88 to 1.22). Other suggested risk factors for gout include obesity, insulin resistance, dyslipidaemia, hypertension, dietary fructose intake, and cardiovascular disorders. Both hyperuricaemia and gout appear to be independently associated with cardiovascular and all-cause mortality in 2010.

Prognosis

We found few reliable data about prognosis or complications of gout. One study found that 3 of 11 (27%) people with untreated gout of the first metatarsophalangeal joint had spontaneous resolution after 7 days. A case series of 614 people with gout who had not received treatment to reduce urate levels, and who could recall the interval between first and second attacks, reported recurrence rates of 62% after 1 year, 78% after 2 years, and 84% after 3 years.

Aims of intervention

For treating gout: to reduce the severity and duration of pain and loss of function, with minimal adverse effects of treatment. For preventing recurrence: to reduce the frequency and severity of recurrent attacks, and minimise the adverse effects of interventions.

Outcomes

For treating gout: symptom severity (pain scores, proportion of people with improved symptoms), adverse effects. For preventing recurrence (over 6 months): number of recurrent episodes per year, severity of recurrent episodes per year, adverse effects.

Methods

BMJ Clinical Evidence search and appraisal September 2013. The following databases were used to identify studies for this systematic review: Medline 1966 to September 2013, Embase 1980 to September 2013, and The Cochrane Database of Systematic Reviews 2013, issue 9 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published systematic reviews and RCTs, at least single-blinded, and containing more than 20 individuals, of whom more than 80% were followed up. For question 1, there was no minimum length of follow-up required to include studies. For question 2, there was a minimum length of follow-up of 6 months, except for xanthine oxidase inhibitors plus prophylactic drugs, where the minimum length of follow-up was 3 months. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the MHRA, which are added to the reviews as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Gout.

Important outcomes	Recurrence of gout, Symptom severity
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of treatments for acute gout?
2 (227)	Symptom severity	Colchicine versus placebo	4	–1	0	–1	0	Low	Quality point deducted for poor follow-up in 1 RCT; directness point deducted for narrow inclusion criteria in 1 RCT
2 (210)	Symptom severity	Corticosteroids versus NSAIDs	4	0	–1	0	0	Moderate	Consistency point deducted for different results at different end points
1 (30)	Symptom severity	NSAIDs versus placebo	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and statistical flaws; consistency point deducted for conflicting results at different end points
8 (1126)	Symptom severity	NSAIDs versus each other	4	–1	0	–1	0	Low	Quality point deducted for incomplete reporting; directness point deducted for differences in regimens between studies and small number of comparisons
What are the effects of xanthine oxidase inhibitors to prevent gout in people with prior acute episodes?
1 (689)	Recurrence of gout	Xanthine oxidase inhibitors versus placebo	4	–1	–1	0	0	Low	Quality point deducted for incomplete reporting of results; consistency point deducted for different results at different time points
3 (at least 2325)	Recurrence of gout	Xanthine oxidase inhibitors versus each other	4	0	–1	0	0	Moderate	Consistency point deducted for different results at different time points and different doses
1 (43)	Recurrence of gout	Xanthine oxidase inhibitors alone versus xanthine oxidase inhibitors plus prophylactic drugs	4	–2	0	0	0	Low	Quality points deducted for sparse data and for uncertainty about basis of statistical analysis

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We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Likert Scale: A method of measuring attitudes that asks respondents to indicate their degree of agreement or disagreement with statements, according to a scoring system (usually 5 points). For example, subjects may be asked to rate their pain on a scale where none = 0, mild = 1, moderate = 2, severe = 3, and extreme = 4.
Low-quality evidence: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Moderate-quality evidence: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Very low-quality evidence: Any estimate of effect is very uncertain.
Visual Analogue Scale (VAS): A commonly used scale in pain assessment. It is a 10-cm horizontal or vertical line with word anchors at each end, such as 'no pain' and 'pain as bad as it could be'. The person is asked to make a mark on the line to represent pain intensity. This mark is converted to distance in either centimetres or millimetres from the 'no pain' anchor to give a pain score that can range from 0–10 cm or 0–100 mm.

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2015 Mar 19;2015:1120.

Colchicine (oral) for treating acute gout

Summary

Colchicine may be more effective than placebo at improving symptoms in acute gout. Its use is limited by the high incidence of adverse effects, although these may be much reduced with low-dose colchicine regimens.

Low-dose colchicine may also be effective at reducing pain in gout and may produce fewer adverse effects than high-dose colchicine.

Benefits and harms

Colchicine versus placebo:

We found one systematic review (search date 2006), which found one RCT. We found one subsequent RCT.

Symptom severity

Colchicine compared with placebo Colchicine may be more effective than placebo at reducing pain at 48 hours, and may increase the proportion of people with 50% or more reduction in pain at 24 hours, in people with gout (low-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Pain
RCT	43 hospital inpatients with acute gout confirmed by synovial fluid examination, aged 55–91 years, 40/43 (93%) men In review	Pain assessed on a 10-cm Visual Analogue Scale; proportion of people with at least 50% improvement in pain 48 hours 16/22 (73%) with colchicine (1 mg followed by 0.5 mg every 2 hours as tolerated or until complete response) 8/21 (36%) with placebo	RR 2.00 95% CI 1.09 to 3.68 P <0.05	Small effect size	colchicine
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Proportion of people with at least 50% pain reduction without rescue medication 24 hours 17/52 (33%) with high-dose colchicine (4.8 mg orally, given over 6 hours) 9/58 (16%) with placebo	OR 2.64 95% CI 1.06 to 6.62 P = 0.034	Moderate effect size	high-dose colchicine
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Proportion of people with at least 50% pain reduction without rescue medication 24 hours 28/74 (40%) with low-dose colchicine (1.8 mg orally, given over 1 hour) 9/58 (16%) with placebo	OR 3.31 95% CI 1.41 to 7.77 P = 0.005	Moderate effect size	low-dose colchicine

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Adverse effects

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Adverse effects
RCT	43 hospital inpatients with acute gout confirmed by synovial fluid examination, aged 55–91 years, 40/43 (93%) men	Proportion of people with nausea, diarrhoea, or vomiting 22/22 (100%) with colchicine 5/21 (24%) with placebo	Significance assessment not reported
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Adverse effects 40/52 (77%) with high-dose colchicine (4.8 mg orally, given over 6 hours) 16/58 (27%) with placebo	OR 9.0 95% CI 3.8 to 21.2	Large effect size	placebo
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Adverse effects 27/74 (37%) with low-dose colchicine (1.8 mg orally, given over 1 hour) 16/58 (27%) with placebo	OR 1.5 95% CI 0.7 to 3.2		Not significant
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Gastrointestinal adverse effects 40/52 (77%) with high-dose colchicine given over 6 hours (4.8 mg orally) 12/59 (20%) with placebo	OR 13.1 95% CI 5.3 to 32.3	Large effect size	placebo
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Gastrointestinal adverse effects 19/74 (26%) with low-dose colchicine given over 1 hour (1.8 mg orally) 12/59 (20%) with placebo	OR 1.4 95% CI 0.6 to 3.1		Not significant
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Severe intensity adverse effects 10/52 (19%) with high-dose colchicine (4.8 mg orally, given over 6 hours) 1/59 (2%) with placebo	OR 13.8 95% CI 1.7 to 112	Large effect size	placebo
RCT 3-armed trial	575 people who were able to start treatment within 12 hours of a gout attack, randomised between attacks; 184 people who subsequently developed acute gout included in analysis (see Further information on studies)	Severe intensity adverse effects 0/74 (0%) with low-dose colchicine (1.8 mg, given over 1 hour) 1/59 (2%) with placebo	Significance assessment not reported

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Colchicine versus NSAIDs:

We found one systematic review (search date 2006), which found no RCTs. We found no subsequent RCTs.

Colchicine versus corticosteroids:

We found one systematic review (search date 2006), which found no RCTs. We found no subsequent RCTs.

Further information on studies

The RCT found that 5/21 (24%) people taking placebo developed nausea (significance assessment not performed). The 50 percent improvement in pain occurred before diarrhoea and vomiting in 9/22 (41%) people, after the onset of diarrhoea and vomiting in 12/22 (55%) people, and at the same time in 1/22 (5%) people.

This RCT included both men and postmenopausal women, aged at least 18 years, with at least two attacks of gout in the previous year, who met ACR classification criteria. The RCT randomised 575 people (95% male, mean age 51 years) to take either low-dose colchicine, high-dose colchicine, or placebo if they had an acute gout flare during the study timeframe. A total of 185/575 (32%) randomised people experienced a confirmed gout flare and took the medication, and were included in the analysis.

The RCT found that high-dose colchicine significantly increased incidence of overall adverse effects and gastrointestinal adverse effects compared with low-dose colchicine (overall adverse effects: OR 5.8, 95% CI 2.6 to 12.9; gastrointestinal adverse effects: OR 9.6, 95% CI 4.2 to 22.1).

Comment

Clinical guide

Colchicine has been used since antiquity to treat gout. A large number of observational studies support its use. Although it is likely to be beneficial, it has a narrow benefit-to-toxicity ratio that limits use of higher doses in people with gout. Lower-dose colchicine regimens that typically use 1.5 mg to 2.0 mg over 24 hours may have fewer adverse effects than higher doses and still be effective.

Substantive changes

No new evidence

BMJ Clin Evid. 2015 Mar 19;2015:1120.

Corticosteroids

Summary

There is a lack of evidence from RCTs concerning the effectiveness of intra-articular or parenteral corticosteroids to improve symptoms in acute gout.

Oral corticosteroids seem as effective as NSAIDs and may have fewer short-term adverse events.

Benefits and harms

Corticosteroids versus placebo:

We found one systematic review (search date 2007), which identified no RCTs. We found no subsequent RCTs.

Corticosteroids versus NSAIDs:

We found two systematic reviews. The first review (search date 2007) found one RCT that compared oral prednisolone with indometacin. We found one subsequent RCT that compared oral prednisolone with naproxen. The second review (search date 2012) searched for RCTs or controlled clinical trials of intra-articular glucocorticoids for acute gout, but failed to identify any studies.

Symptom severity

Corticosteroids compared with NSAIDs Corticosteroids and NSAIDs seem to be equally effective at reducing pain in people with acute arthritis suggestive of gout (moderate-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Pain
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Mean rate of decrease in pain score (assessed on a 100-mm Visual Analogue Scale) 2 hours 6.4 mm/hour with indometacin 9.5 mm/hour with prednisolone	Mean difference +3.2 mm/hour 95% CI –0.78 mm/hour to +7.14 mm/hour P = 0.12 Equivalence satisfied (see Further information on studies)		Not significant
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Mean rate of decrease in pain score (assessed on a 100-mm Visual Analogue Scale) days 1 to 14 0.3 mm/day with indometacin 0.7 mm/day with prednisolone	Mean difference 0.5 mm/day 95% CI 0.03 mm/day to 0.89 mm/day P = 0.04	Effect size not calculated	prednisolone
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Mean rate of decrease in pain score (assessed on a 100-mm Visual Analogue Scale) 2 weeks with indometacin with prednisolone Absolute results not reported	Reported as not significant P value not reported		Not significant
RCT	120 people with acute gout confirmed by identification of monosodium urate crystals in synovial fluid from the affected joint; mean age 57 years, 89% men	Pain reduction (assessed on a 100-mm Visual Analogue Scale, higher values indicating greater pain) 90 hours 44.7 mm with prednisolone 46.0 mm with naproxen	Difference between groups +1.3 mm 95% CI –9.8 to +7.1 Equivalence satisfied (see Further information on studies)		Not significant
RCT	120 people with acute gout confirmed by identification of monosodium urate crystals in synovial fluid from the affected joint; mean age 57 years, 89% men	Mean pain reduction (assessed by 100-mm Visual Analogue Scale, higher numbers indicating greater pain) at each of 8 follow-up time points up to 90 hours –5.6 mm with prednisolone –5.8 mm with naproxen	Difference between groups +1.57 mm 95% CI –8.65 to +11.78 Equivalence not satisfied (see Further information on studies)		Not significant

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Adverse effects

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Adverse effects
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Total adverse effects 29/46 (63%) with indometacin 12/44 (27%) with prednisolone	P = 0.0007	Effect size not calculated	prednisolone
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Epigastric pain 14/30 (30%) with indometacin 0/44 (0%) with prednisolone	P <0.0001	Effect size not calculated	prednisolone
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Gastrointestinal haemorrhage 5/46 (11%) with indometacin 0/44 (0%) with prednisolone	P <0.05	Effect size not calculated	prednisolone
RCT	90 people with an acute arthritis suggestive of gout, 74 men, mean age 65 years In review	Hospital admission rates because of serious adverse effects 7/46 (15%) with indometacin 0/44 (0%) with prednisolone	P <0.007	Effect size not calculated	prednisolone
RCT	120 people with acute gout confirmed by identification of monosodium urate crystals in synovial fluid from the affected joint; mean age 57 years, 89% men	Adverse effects 34% with prednisolone 37% with naproxen Absolute numbers not reported	P = 0.42		Not significant
RCT	120 people with acute gout confirmed by identification of monosodium urate crystals in synovial fluid from the affected joint; mean age 57 years, 89% men	Gastric or abdominal pain 15% with prednisolone 15% with naproxen Absolute numbers not reported

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Corticosteroids versus colchicine:

We found one systematic review (search date 2007), which found no RCTs. We found no subsequent RCTs.

Further information on studies

This RCT has some of the features of an equivalence study with a predefined limit for equivalence (±13 mm visual analogue scale). This criterion for equivalence was satisfied for this outcome.

The RCT comparing prednisolone versus naproxen was designed to show whether the two treatments were equivalent, rather than whether one was superior to the other. Whether the 'not significant' result means that the two treatments are equivalent in effectiveness depends on the 95 percent confidence interval of the effect falling within the predefined margin of equivalence (in this RCT arbitrarily chosen as 10%). For the outcome of pain reduction at 90 hours, the RCT found that the treatments were equivalent; however, for the outcome of mean pain reduction at eight follow-up times up to 90 hours; although the difference between groups was not significant, the result was inconclusive with respect to whether the treatments were equivalent.

Comment

Clinical guide

Both high-dose oral non-steroidal anti-inflammatory drugs (NSAIDs) and high-dose colchicine have a high incidence of adverse events. Adverse events from occasional short courses of oral corticosteroids are uncommon. Two RCTs comparing NSAIDs and prednisolone found them to have similar effectiveness. In one of these RCTs, significantly more people in the NSAID groups developed serious adverse effects. Oral corticosteroids may be preferable to either NSAIDs or high-dose colchicine for the occasional treatment of acute gout.

There is no evidence from RCTs to evaluate the safety and efficacy of intra-articular glucocorticoids in acute gout.

Substantive changes

Corticosteroids One systematic review added. Categorisation unchanged (unknown effectiveness), as there remains insufficient evidence to judge the effects of this intervention.

BMJ Clin Evid. 2015 Mar 19;2015:1120.

Non-steroidal anti-inflammatory drugs (NSAIDs)

Summary

There is a lack of evidence from RCTs on the effectiveness of NSAIDs to reduce pain and tenderness in an acute attack of gout, although they are commonly used in clinical practice. They are associated with increased risks of gastrointestinal, and possible cardiovascular, adverse effects.

Indometacin may be more effective than celecoxib, and equally effective as etoricoxib, at reducing pain in people with acute gout; although indometacin may be associated with an increased risk of adverse effects compared with etoricoxib.

NSAIDs seem as effective as oral corticosteroids, but may be associated with more short-term adverse effects.

We found no direct information from RCTs about whether NSAIDs are better than oral colchicine in people with gout.

Benefits and harms

NSAIDs versus placebo:

We found one systematic review (search date 2005),which found one RCT.

Symptom severity

NSAIDs compared with placebo NSAIDs (tenoxicam) may be more effective at reducing pain at 1 day, but may be no more effective at reducing pain at 4 days, in people with acute gout (very low-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Pain
RCT	30 people, aged 21–70 years, with gout of the knee, ankle, wrist, big toe, or elbow In review	Proportion of people showing at least a 50% reduction in pain (pain assessed on a 4-point scale: 'disappeared', 'improved by at least 50%', 'unchanged or improved by <50%', or 'increased') 1 day 10/15 (67%) with tenoxicam 4/15 (26%) with placebo	P <0.05	Effect size not calculated	tenoxicam
Tenderness
RCT	30 people, aged 21–70 years, with gout of the knee, ankle, wrist, big toe, or elbow In review	Proportion of people showing at least a 50% reduction in tenderness (assessed on a 4-point scale: 'disappeared', 'improved by at least 50%', 'unchanged or improved by <50%', or 'increased') 1 day 6/15 (40%) with tenoxicam 1/15 (7%) with placebo	P <0.05	Effect size not calculated	tenoxicam
Pain on mobilisation
RCT	30 people, aged 21–70 years, with gout of the knee, ankle, wrist, big toe, or elbow In review	Proportion of people showing at least a 50% reduction in pain on mobilisation (assessed on a 4-point scale: 'disappeared', 'improved by at least 50%', 'unchanged or improved by <50%', or 'increased') 1 day 4/15 (27%) with tenoxicam 1/15 (7%) with placebo	P <0.05	Effect size not calculated	tenoxicam
Physician-rated efficacy
RCT	30 people, aged 21–70 years, with gout of the knee, ankle, wrist, big toe, or elbow In review	Proportion of people with improvement rated as 'good or excellent' 4 days 7/15 (47%) with tenoxicam 4/15 (27%) with placebo	Reported as not significant P value not reported		Not significant

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Adverse effects

No data from the following reference on this outcome.

NSAIDs versus each other:

We found one systematic review (search date 2005), which identified nine RCTs comparing different NSAIDs with each other. Two of the high-quality RCTs identified in the review were designed as equivalence studies comparing indometacin 50 mg three times daily with etoricoxib 120 mg daily. Four of the remaining seven RCTs identified in the systematic review satisfied our inclusion criteria. We found two subsequent RCTs.

Symptom severity

NSAIDs compared with each other Indometacin may be more effective than celecoxib, and equally effective as etoricoxib, at reducing pain in people with acute gout. However, we don’t know how they compare with each other in reducing tenderness and joint swelling (low-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Pain
RCT	189 people, gout for <48 hours, who had previously responded to NSAIDs, 93% male, mean age 52 years In review	Pain rating (measured on Likert Scale: 0 = no pain to 4 = extreme pain) days 2–5 with indometacin (50 mg 3-times daily) with etoricoxib (120 mg/day) Absolute results not reported	Difference: –0.08 95% CI –0.29 to +0.13 Equivalence satisfied (see Further information on studies)		Not significant
RCT	150 men, gout for <24 hours, mean age 49 years In review	Pain rating (measured on Likert Scale: 0 = no pain to 4 = extreme pain) days 2–5 with indometacin (50 mg 3-times daily) with etoricoxib (120 mg/day) Absolute results not reported	Difference: +0.11 95% CI –0.14 to +0.35 Equivalence satisfied (see Further information on studies)		Not significant
RCT	61 people, aged 18–75 years In review	Mean pain scores assessed on a scale 0 to 5 (higher scores indicating worse pain) day 2 2.6 with etodolac (300 mg twice-daily) 2.8 with naproxen (500 mg twice-daily)	Reported as not significant P value not reported		Not significant
RCT	61 people, aged 18–75 years In review	Mean pain scores assessed on a scale 0 to 5 (higher scores indicating worse pain) day 4 1.8 with etodolac (300 mg twice-daily) 2.0 with naproxen (500 mg twice-daily)	Reported as not significant P value not reported		Not significant
RCT	61 people, aged 18–75 years In review	Mean pain scores assessed on a scale 0 to 5 (higher scores indicating worse pain) day 7 1.4 with etodolac (300 mg twice-daily) 1.4 with naproxen (500 mg twice-daily)	Reported as not significant P value not reported		Not significant
RCT	60 people, aged 18 to 75 years In review	Pain (as assessed on a 5-point rating scale: 1 = no pain to 5 = very severe pain) days 1–7 with etodolac (300 mg twice-daily) with naproxen (500 mg twice-daily) Absolute results reported graphically	Reported as not significant P value not reported		Not significant
RCT	59 people, gout for <48 hours, aged 35 to 88 years In review	Mean pain scores (as assessed on a 4-point scale: 0 = no pain to 3 = severe pain) day 2 0.9 with indometacin (up to 225 mg for 1 day in divided doses, followed by 50 mg 3-times daily) 1.1 with ketoprofen (450 mg in divided doses for 1 day, followed by 100 mg 3-times daily)	Reported as not significant P value not reported		Not significant
RCT	59 people, gout for <48 hours, aged 35 to 88 years In review	Mean pain scores (as assessed on a 4-point scale: 0 = no pain to 3 = severe pain) day 5 0.8 with indometacin (up to 225 mg for 1 day in divided doses, followed by 50 mg 3-times daily) 1.3 with ketoprofen (450 mg in divided doses for 1 day, followed by 100 mg 3-times daily)	Reported as not significant P value not reported		Not significant
RCT	59 people, gout for <48 hours, aged 35 to 88 years In review	Mean pain scores (as assessed on a 4-point scale: 0 = no pain to 3 = severe pain) day 8 0.3 with indometacin (up to 225 mg for 1 day in divided doses, followed by 50 mg 3-times daily) 0.4 with ketoprofen (450 mg in divided doses for 1 day, followed by 100 mg 3-times daily)	Reported as not significant P value not reported		Not significant
RCT	29 people In review	Proportion of people with improved pain 2 days 11/12 (92%) with indometacin (50 mg 4-times daily for 4 days, followed by 25 mg 4-times daily for 5 days) 11/12 (92%) with flurbiprofen (100 mg 4-times daily for 1 day, followed by 50 mg 4-times daily for 5 days)	Reported as not significant P value not reported		Not significant
RCT	178 adults, acute gout for <48 hours	Mean pain reduction (measured on Likert Scale: 0 = no pain to 4 = extreme pain days 2 to 5 –1.99 with etoricoxib (120 mg/day for 5 days) –2.02 with indometacin (75 mg twice-daily for 5 days)	Mean difference 0.03 95% CI –0.19 to 0.25 P = 0.57		Not significant
RCT 4-armed trial	400 adults, acute gouty arthritis for 48 hours or less	Mean pain reduction (measured on Likert Scale: 0 = no pain to 4 = extreme pain) day 2 –1.14 with celecoxib (50 mg twice-daily) –1.62 with indometacin (50 mg 3-times daily)	Mean difference 0.57 95% CI 0.29 to 0.84 P <0.0001	Effect size not calculated	indometacin
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean pain reduction (measured on Likert Scale: 0 = no pain to 4 = extreme pain) day 2 –1.23 with celecoxib (400 mg followed by 200 mg later on day 1, and then 200 mg twice-daily for 7 days) –1.62 with indometacin (50 mg 3-times daily)	Mean difference 0.33 95% CI 0.05 to 0.60 P = 0.0196	Effect size not calculated	indometacin
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean pain reduction (measured on Likert Scale: 0 = no pain to 4 = extreme pain) day 2 –1.51 with celecoxib (800 mg followed by 400 mg later on day 1, and then 400 mg twice-daily for 7 days) –1.62 with indometacin (50 mg 3-times daily)	Mean difference 0.11 95% CI –0.17 to +0.39 P = 0.44		Not significant
Tenderness
RCT	178 adults, acute gout for <48 hours	Mean joint tenderness reduction (measured on a 4 point scale: 0 = no tenderness to 3 = patient complains of pain, winces, and withdraws) days 2 to 5 –1.99 with etoricoxib –2.03 with indometacin	P = 0.73		Not significant
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean joint tenderness reduction (measured on a 4-point scale: 0 = no tenderness to 4 = patient complains of pain, winces, and withdraws) 1.74 with celecoxib (50 mg twice-daily) 1.64 with indometacin (50 mg 3-times daily)	P value not reported
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean joint tenderness reduction (measured on a 4 point scale: 0 = no tenderness to 4 = patient complains of pain, winces, and withdraws) 1.66 with celecoxib 400 mg (followed by 200 mg later on day 1, and then 200 mg twice-daily for 7 days) 1.64 with indometacin (50 mg 3-times daily)	P value not reported
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean joint tenderness reduction (measured on a 4-point scale: 0 = no tenderness to 4 = patient complains of pain, winces, and withdraws) 1.94 with celecoxib 800 mg (followed by 400 mg later on day 1, and then 400 mg twice-daily for 7 days) 1.64 with indometacin (50 mg 3-times daily)	P value not reported
Joint swelling
RCT	178 adults, acute gout for <48 hours	Mean joint swelling reduction (measured on a 4-point scale: 0 = no swelling to 3 = bulging beyond joint margins) days 2–5 –1.92 with etoricoxib –1.90 with indometacin	Mean difference 0.02 P = 0.74		Not significant
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean joint swelling reduction (measured on a 4-point scale: 0 = no swelling to 3 = bulging beyond joint margins) 1.55 with celecoxib (50 mg twice-daily) 1.58 with indometacin (50 mg 3-times daily)	P value not reported
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Mean joint swelling reduction (measured on a 4-point scale: 0 = no swelling to 3 = bulging beyond joint margins) 1.63 with celecoxib (400 mg followed by 200 mg later on day 1, and then 200 mg twice-daily) 1.58 with indometacin (50 mg 3-times daily)	P value not reported
RCT 4-armed trial	400 adults with acute gouty arthritis for ≤48 hours	Mean joint swelling reduction (measured on a 4-point scale: 0 = no swelling to 3 = bulging beyond joint margins) 1.78 with celecoxib (800 mg followed by 400 mg later on day 1, and then 400 mg twice-daily) 1.58 with indometacin (50 mg 3-times daily)	P value not reported

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Adverse effects

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Adverse effects
RCT	189 people, gout for <48 hours, who had previously responded to NSAIDs, 93% male, mean age 52 years In review	Proportion of people reporting at least 1 adverse event 49/86 (57%) with indometacin (50 mg 3-times daily) 45/103 (44%) with etoricoxib (120 mg/day)	P = 0.08		Not significant
RCT	189 people, gout for <48 hours, who had previously responded to NSAIDs, 93% male, mean age 52 years In review	Drug-related adverse events 32/86 (37%) with indometacin (50 mg 3-times daily) 17/103 (17%) with etoricoxib (120 mg/day)	P = 0.002	Effect size not calculated	etoricoxib
RCT	150 men, gout for <24 hours, mean age 49 years In review	Proportion of people with adverse events 35/75 (47%) with indometacin (50 mg 3-times daily) 17/75 (23%) with etoricoxib (120 mg/day)	P = 0.003	Effect size not calculated	etoricoxib
RCT	178 adults, acute gout for <48 hours	Proportion of patients with serious adverse event 0/89 (0%) with etoricoxib 1/89 (1%) with indometacin	P >0.9999		Not significant
RCT	178 adults, acute gout for <48 hours	Proportion of patients with adverse event leading to withdrawal 2/89 (2%) with etoricoxib 0/89 (0%) with indometacin	P value not reported
RCT	178 adults, acute gout for <48 hours	Proportion of patients with non-serious drug-related gastrointestinal adverse events with etoricoxib with indometacin	Reported as not significant		Not significant
RCT 4-armed trial	400 adults with acute gouty arthritis for 48 hours or less	Proportion of patients with severe adverse event 5/101 (5%) with celecoxib (50 mg twice-daily) 3/99 (3%) with 400 mg celecoxib (followed by 200 mg later on day 1, and then 200 mg twice-daily) 2/98 (2%) with 800 mg celecoxib (followed by 400 mg later on day 1, and then 400 mg twice-daily) 1/102 (1%) with indometacin	P value not reported
RCT 4-armed trial	400 adults with acute gouty arthritis for ≤48 hours	Proportion of patients with upper gastrointestinal adverse events (pain, dyspepsia, nausea) 5/101 (5%) with celecoxib (50 mg twice-daily) 0/99 (0%) with 400 mg celecoxib (followed by 200 mg later on day 1, and then 200 mg twice-daily) 4/98 (4%) with 800 mg celecoxib (followed by 400 mg later on day 1, and then 400 mg twice-daily) 11/102 (11%) with indometacin	P value not reported

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No data from the following reference on this outcome.

NSAIDs versus corticosteroids:

See option on Corticosteroids.

NSAIDs versus colchicine:

See option on Colchicine.

Further information on studies

The RCT comparing tenoxicam versus placebo conducted multiple significance tests, and no adjustment was reported for this.

These RCTs comparing etoricoxib versus indometacin were designed as equivalence trials to show whether the two treatments were equivalent, rather than whether one was superior to the other. Whether the 'not significant' result means that the two treatments were equivalent in effectiveness depends on the 95% confidence interval of the effect falling within the predefined margin of equivalence (in both these RCTs, defined as within ±0.5 units). For the outcome of pain at days 2 to 5, both RCTs found that etoricoxib and indometacin were equivalent.

No differences in important adverse effect rates were found.

Comment

NSAIDs versus each other

Phenylbutazone and indometacin were established as treatments for gout based on uncontrolled studies. Only the comparisons between etoricoxib and indometacin and celecoxib and indometacin were powered to show equivalence in efficacy between the two compounds tested. We found six RCTs comparing phenylbutazone with other NSAIDs. These were not considered further because phenylbutazone for gout has been restricted in many countries as it can cause aplastic anaemia and other serious adverse effects.

We found one RCT (93 people) comparing indometacin with azapropazone. We have not considered this further as use of azapropazone has been restricted because of a high incidence of gastrointestinal, renal, and hepatic adverse events.

We found one RCT (62 people) comparing meloxicam with diclofenac and with rofecoxib. We have not considered this study further as rofecoxib has been withdrawn worldwide because of cardiovascular adverse effects. The RCT was not designed to compare meloxicam versus diclofenac directly.

We found one RCT (235 people) comparing lumaricoxib with indometacin. This non-inferiority study found lumaricoxib to be as effective as indometacin at relieving pain. We have not considered this study further as lumaricoxib has since been withdrawn worldwide because of hepatic adverse effects.

Clinical guide

Although there is very little RCT evidence to support their use, traditional NSAIDs are commonly used to treat gout and are recommended in guidelines. The choice of NSAID probably depends on doctor or patient preference. Adverse effects of NSAIDs, including COX-2 inhibitors, often do not manifest early in treatment. However, it is usual to prescribe proton pump inhibitors to reduce the incidence of gastrointestinal bleeding because high doses of NSAIDs are used.

The harms of NSAIDs/COX-2 inhibitors are considered in detail elsewhere in BMJ Clinical Evidence and include gastrointestinal ulceration and haemorrhage, and increased cardiovascular risk (see review on NSAIDs).

Substantive changes

Non-steroidal anti-inflammatory drugs (NSAIDs) Two subsequent RCTs added. Categorisation unchanged (unknown effectiveness), as there remains insufficient evidence to judge the effects of this intervention.

BMJ Clin Evid. 2015 Mar 19;2015:1120.

Xanthine oxidase inhibitors

Summary

It’s not clear from the evidence from RCTs if xanthine oxidase inhibitors are effective at reducing the risk of recurrent attacks in the long term when compared with placebo or other treatments.

Higher doses of febuxostat may increase the incidence of gout flares over the first 28 weeks of treatment compared with placebo, and compared with allopurinol.

Colchicine may reduce the risk of an attack in a person starting allopurinol treatment.

CAUTION: the MHRA advises (June 2012) that there have been rare but serious reports of hypersensitivity reactions, including Stevens-Johnson syndrome and acute anaphylactic shock, with febuxostat.

Benefits and harms

Xanthine oxidase inhibitors versus placebo:

We found one systematic review (search date 2011), which found two RCTs. The first RCT (1072 people) compared placebo, allopurinol, and different doses of febuxostat. All participants also received naproxen or colchicine during the first 8 weeks of treatment, to reduce the increased incidence of gout flares that can occur when urate-lowering medication is initiated (see Further information on studies). The second RCT only reported outcomes at 28 days and, therefore, did not meet BMJ Clinical Evidence criteria for inclusion here.

Recurrence of gout

Xanthine oxidase inhibitors compared with placebo Febuxostat at higher doses may increase incidence of recurrent gout compared with placebo at 28 weeks, but we don't know whether it is more or less effective at lower doses or in the longer term. We do not know whether allopurinol is more effective than placebo at reducing the recurrence of gout at 8 to 28 weeks (low-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Recurrence of gout
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Incidence of gout flares at 28 weeks 69/134 (51%) with febuxostat 240 mg 27/134 (20%) with placebo	RR 2.56 95% CI 1.76 to 3.72 P <0.00001	Moderate effect size	placebo
RCT 5-armed trial	1072 people with gout, defined using ACR criteria with serum urate 8.0 mg/dL or greater (0.48 mmol/L or greater), aged 18–85 years (mean age 52 years), 94% men In review	Proportion of people requiring treatment for acute gout weeks 8–28 with febuxostat 80 mg with placebo Absolute results not reported	Reported as no significant differences between groups		Not significant
RCT 5-armed trial	1072 people with gout, defined using ACR criteria with serum urate 8.0 mg/dL or greater (0.48 mmol/L or greater), aged 18–85 years (mean age 52 years), 94% men In review	Proportion of people requiring treatment for acute gout weeks 8–28 with febuxostat 120 mg with placebo Absolute results not reported	Reported as no significant differences between groups		Not significant
RCT 5-armed trial	1072 people with gout, defined using ACR criteria with serum urate 8.0 mg/dL or greater (0.48 mmol/L or greater), aged 18–85 years (mean age 52 years), 94% men In review	Proportion of people requiring treatment for acute gout weeks 8–28 with febuxostat 240 mg with placebo Absolute results not reported	Reported as no significant differences between groups		Not significant
RCT 5-armed trial	1072 people with gout, defined using ACR criteria with serum urate 8.0 mg/dL or greater (0.48 mmol/L or greater) aged 18–85 years (mean age 52 years), 94% men In review	Proportion of people requiring treatment for acute gout weeks 8–28 with allopurinol 300 mg with placebo Absolute results not reported	Reported as no significant differences between groups		Not significant

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Adverse effects

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Adverse effects
Systematic review	268 people with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Proportion of people with serious adverse effects at 28 weeks 5/134 (4%) with febuxostat 240 mg 2/134 (2%) with placebo	RR 2.50 95% CI 0.49 to 12.66		Not significant
Systematic review	268 people with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Proportion of people with skin reaction at 28 weeks 6/134 (4.5%) with febuxostat 240 mg 7/134 (5.2%) with placebo	RR 0.86 95% CI 0.30 to 2.48		Not significant

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Xanthine oxidase inhibitors versus each other:

We found one systematic review (search date 2012), which found three RCTs. The first RCT compared three interventions: allopurinol 300 mg daily, febuxostat 80 mg daily, and febuxostat 120 mg daily. The second RCT compared placebo, allopurinol, and febuxostat (80 mg, 120 mg, or 240 mg). All participants in the first and the second RCTs also received naproxen or colchicine during the first 8 weeks of treatment, to reduce the increased incidence of gout flares that can occur when urate-lowering medication is initiated. The third RCT compared febuxostat and allopurinol. It included participants who had been involved in the first and second RCT, although the systematic review excluded these patients from their analysis. All participants also received naproxen and colchicine for the 6-month duration of the trial (see Further information on studies).

Recurrence of gout

Xanthine oxidase inhibitors compared with each other Allopurinol and febuxostat seem to be similarly effective at preventing recurrence of gout at 8 to 52 weeks. Higher doses of febuxostat may increase the incidence of gout flares over the first 28 weeks of treatment compared with allopurinol (moderate-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Recurrence of gout
Systematic review	People with preliminary ACR criteria for gout and serum uric acid ≥ 8.0 mg/dL Data from 1 RCT	Incidence of gout flares at 24 weeks 26/659 (3.9%) with febuxostat 40 mg 27/665 (4.1%) with allopurinol	RR 0.97 95% CI 0.57 to 1.65		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 3 RCTs in this analysis	Incidence of gout flares at 8, 24, or 52 weeks 260/1158 (22%) with febuxostat 80 mg 238/1167 (20%) with allopurinol	RR 1.12 95% CI 0.98 to 1.27		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 2 RCTs in this analysis	Incidence of gout flares at 8 weeks or 52 weeks 247/484 (51%) with febuxostat 120 mg 211/502 (42%) with allopurinol	RR 1.29 95% CI 0.87 to 1.91		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Incidence of gout flares at 28 weeks 69/134 (52%) with febuxostat 240 mg 61/268 (23%) with allopurinol	RR 2.26 95% CI 1.72 to 2.98	Moderate effect size	allopurinol

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Adverse effects

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Adverse effects
RCT 3-armed trial	760 people with a history of gout, mean age 52 years, 96% male In review	Deaths 0/253 (0%) with allopurinol 2/256 (0.8%) with febuxostat 80 mg 2/251 (0.8%) with febuxostat 120 mg	P = 0.31		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0mg/dL or higher Data from 1 RCT	Proportion of people with serious adverse effects at 24 weeks 19/757 (3%) with febuxostat 40 mg 31/756 (4%) with allopurinol	RR 0.61 95% CI 0.35 to 1.07		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0mg/dL or higher Data from 1 RCT	Proportion of people with skin reaction at 24 weeks 44/757 (6%) with febuxostat 40 mg 55/756 (7%) with allopurinol	RR 0.8 95% CI 0.54 to 1.17		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 3 RCTs in this analysis	Proportion of people with serious adverse effects at 24–28 or 52 weeks 50/1279 (4%) with febuxostat 80 mg 57/1277 (5%) with allopurinol	RR 0.88 95% CI 0.55 to 1.42		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 3 RCTs in this analysis	Proportion of people with skin reaction at 24–28 or 52 weeks 57/1279 (5%) with febuxostat 80 mg 73/1277 (6%) with allopurinol	RR 0.78 95% CI 0.56 to 1.09		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 3 RCTs in this analysis	Proportion of people with hypertension at 24–28 or 52 weeks 13/1279 (1.0%) with febuxostat 80 mg 3/1277 (0.2%) with allopurinol	RR 4.35 95% CI 1.25 to 15.09	Moderate effect size	allopurinol
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 2 RCTs in this analysis	Proportion of people with serious adverse effects at 28 or 52 weeks 30/520 (6%) with febuxostat 120 mg 26/521 (5%) with allopurinol	RR 1.16 95% CI 0.70 to 1.93		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 2 RCTs in this analysis	Proportion of people with skin reaction at 28 or 52 weeks 18/520 (3.5%) with febuxostat 120 mg 18/521 (3.5%) with allopurinol	RR 1.00 95% CI 0.53 to 1.89		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher 2 RCTs in this analysis	Proportion of people with cardiovascular adverse effects at 28 or 52 weeks 5/520 (1.0%) with febuxostat 120 mg 1/521 (0.2%) with allopurinol	Risk difference 0.01 95% CI 0.00 to 0.02	Effect size not calculated	allopurinol
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Proportion of people with serious adverse effects at 28 weeks 5/134 (4%) with febuxostat 240 mg 7/268 (3%) with allopurinol	RR 1.43 95% CI 0.46 to 4.42		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Proportion of people with skin reaction at 28 weeks 6/134 (4.5%) with febuxostat 240 mg 14/268 (5.2%) with allopurinol	RR 0.86 95% CI 0.34 to 2.18		Not significant
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0mg/dL or higher Data from 1 RCT	Proportion of people with hypertension at 28 weeks 6/134 (5%) with febuxostat 240 mg 3/268 (1%) with allopurinol	RR 4.0 95% CI 1.02 to 15.75	Moderate effect size	allopurinol
Systematic review	People with preliminary ACR criteria for gout and serum uric acid 8.0 mg/dL or higher Data from 1 RCT	Proportion of people with diarrhoea at 28 weeks 18/134 (13%) with febuxostat 240 mg 17/268 (6%) with allopurinol	RR 2.12 95% CI 1.13 to 3.97	Moderate effect size	allopurinol

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Xanthine oxidase inhibitors alone versus xanthine oxidase inhibitors plus prophylactic drugs:

We found one systematic review (search date 2012), which found no RCTs. We found one additional RCT comparing colchicine 0.6 mg twice daily versus placebo in people starting allopurinol as prevention for recurrent gout. Treatment was continued for 3 months after serum urate reached normal levels. The dose was reduced to once daily in people with renal insufficiency or gastrointestinal adverse effects.

Recurrence of gout

Xanthine oxidase inhibitors alone compared with xanthine oxidase inhibitors plus prophylactic drugs Initiating treatment with allopurinol alone may be less effective than initiating treatment with allopurinol during colchicine prophylaxis at reducing the risk of recurrent attacks of gout at 6 months (low-quality evidence).

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Recurrence of gout
RCT	43 people starting treatment with allopurinol for chronic gouty arthritis	Proportion of people with at least 1 attack 6 months 7/21 (33%) with allopurinol plus colchicine (12 attacks in total) 17/22 (77%) with allopurinol plus placebo (65 attacks in total)	P = 0.008 The authors report that the finding was significant, but the basis of the statistical analysis was not clear	Effect size not calculated	allopurinol plus colchicine
RCT	43 people starting treatment with allopurinol for chronic gouty arthritis	Severity of attacks (median score on Visual Analogue Scale [scale range not reported]) 6 months 3.64 with allopurinol plus colchicine 5.08 with allopurinol plus placebo	P = 0.018	Effect size not calculated	allopurinol plus colchicine
RCT	43 people starting treatment with allopurinol for chronic gouty arthritis	Mean duration of attacks 6 months 6.00 days with allopurinol plus colchicine 5.56 days with allopurinol plus placebo	P = 0.566		Not significant

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Adverse effects

Ref (type)	Population	Outcome, Interventions	Results and statistical analysis	Effect size	Favours
Adverse effects
RCT	43 people starting treatment with allopurinol for chronic gouty arthritis	Diarrhoea 38% with allopurinol plus colchicine 5% with allopurinol plus placebo Absolute numbers not reported	P = 0.009	Effect size not calculated	allopurinol plus placebo

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Further information on studies

The systematic review reported that total discontinuation rates were significantly higher in the febuxostat 80 mg group compared to placebo (RR 1.4; 95% CI 1.0 to 2.0). Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol (RR 1.5; 95% CI 1.2 to 1.8, and RR 2.6; 95% CI 2.0 to 3.3, respectively). Discontinuations due to adverse events were similar across groups.

The systematic review also reported on two open-label long-term follow-up studies, although only one of these studies had a control group. After 3 years of follow-up there were no statistically significant differences regarding effectiveness and harms between febuxostat 80 mg or 120 mg and allopurinol groups (adverse event rate per 100 patient-years 227, 216, and 246, respectively). No increase in gout flares was observed in the long-term follow-up study with febuxostat compared to allopurinol.

This RCT compared five interventions: placebo; allopurinol 300 mg daily, depending on renal function (10/268 received 100 mg/day because of impaired renal function); febuxostat 80 mg daily; febuxostat 120 mg daily; or febuxostat 240 mg daily. Participants who had not previously had urate-lowering therapy also received naproxen 250 mg twice daily or colchicine 0.6 mg daily during the first 8 weeks of treatment to reduce the increased incidence of gout flares that can occur when urate-lowering medication is initiated.

The primary outcome for the first RCT included in the systematic review comparing allopurinol with febuxostat was a serum urate of less than 0.36 mmol/L at each of the last three monthly visits. All participants also received naproxen or colchicine during the first 8 weeks of treatment, to reduce the increased incidence of gout flares that can occur when urate-lowering medication is initiated. Both doses of febuxostat significantly increased the proportion of people achieving the primary end point compared with allopurinol (53/251 [21%] with allopurinol v 136/255 [53%] with febuxostat 80 mg v 154/250 [62%] with febuxostat 120 mg; P <0.001 for allopurinol v febuxostat 80 mg and febuxostat 120 mg).

The RCT reported that no one withdrew because of diarrhoea, and all cases resolved when the dose was reduced.

Comment

We found one open RCT comparing colchicine 0.5 mg twice-daily with colchicine 0.5 mg twice-daily plus allopurinol 300 mg once-daily. Three people (10%) allocated to the colchicine plus allopurinol group who did not take allopurinol were included in the colchicine-only group for analysis. In the first year there was no significant difference between treatments in recurrent attacks of gout (10/33 [30%] with colchicine alone v 5/26 [19%] with colchicine plus allopurinol; difference reported as not significant; P value not reported).

Clinical guide

Many experts believe that allopurinol should not normally be started during an attack of gout. There is, however, one small RCT (n = 57) that did not find any difference in outcome between starting allopurinol during an attack or 10 days later.

There is some evidence to support the usual practice of co-prescribing prophylactic drugs, such as colchicine, when starting urate-lowering medication. The focus of this review is the prevention of recurrent gout rather than reducing serum urate. It is not clear how effective xanthine oxidase inhibitors are at reducing the incidence of recurrent gout. If urate-lowering drugs are used, then the dose should be titrated upwards to achieve a target urate level of less than 0.36 mmol/L, which prevents crystal formation and promotes the crystals' dissolution. This process of crystal dissolution may increase incidence of recurrent gout in the short to medium term. Febuxostat seems more effective than allopurinol at reducing serum urate, but does not result in a reduction in recurrent gout over the first year of treatment. Febuxostat might be an alternative for people who cannot tolerate allopurinol.

Substantive changes

Xanthine oxidase inhibitors One systematic review added. Categorisation updated (unknown effectiveness [insufficient evidence compared to placebo]), as there remains insufficient evidence to judge the effects of this intervention.

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PERMALINK

Gout

Martin Underwood

Roles

Abstract

Introduction

Methods and outcomes

Results

Conclusions

Key Points

Clinical context

General background

Focus of the review

Comments on evidence

Search and appraisal summary

Additional information

About this condition

Definition

Table 1.

Incidence/ Prevalence

Aetiology/ Risk factors

Prognosis

Aims of intervention

Outcomes

Methods

Table.

Glossary

Disclaimer

References

Colchicine (oral) for treating acute gout

Summary

Benefits and harms

Colchicine versus placebo:

Symptom severity

Adverse effects

Colchicine versus NSAIDs:

Colchicine versus corticosteroids:

Further information on studies

Comment

Clinical guide

Substantive changes

Corticosteroids

Summary

Benefits and harms

Corticosteroids versus placebo:

Corticosteroids versus NSAIDs:

Symptom severity

Adverse effects

Corticosteroids versus colchicine:

Further information on studies

Comment

Clinical guide

Substantive changes

Non-steroidal anti-inflammatory drugs (NSAIDs)

Summary

Benefits and harms

NSAIDs versus placebo:

Symptom severity

Adverse effects

NSAIDs versus each other:

Symptom severity

Adverse effects

NSAIDs versus corticosteroids:

NSAIDs versus colchicine:

Further information on studies

Comment

NSAIDs versus each other

Clinical guide

Substantive changes

Xanthine oxidase inhibitors

Summary

Benefits and harms

Xanthine oxidase inhibitors versus placebo:

Recurrence of gout

Adverse effects

Xanthine oxidase inhibitors versus each other:

Recurrence of gout

Adverse effects

Xanthine oxidase inhibitors alone versus xanthine oxidase inhibitors plus prophylactic drugs:

Recurrence of gout